ABSTRACT Therapeutic hypothermia (TH) improves neurologic outcomes after CNS injury. Preclinical studies show that mild cooling to ~33C has beneficial effects on the injured brain which involves multiple mechanisms including (but not limited to): fever reduction, decreasing metabolic demand/ATP consumption, decreasing intracellular mediators of apoptosis, and increasing pro-survival proteins. In contrast, TH can also increase the risk of adverse complications like infection, ion disturbances, hyperglycemia, and insulin resistance ? which may increase mortality or worsen brain injury. TH surprisingly has failed to translate in traumatic brain injury (TBI) in either children or adults. Recent clinical trials were done to compare if neurological outcomes were better in cardiac arrest patients treated with mild TH to 33C vs. fever prevention using targeted temperature management (TTM) to ~36C. No difference in neurological outcome was observed - indicating that TH and TTM had similar therapeutic efficacy. Inhibition of fever in both treatment groups may explain those surprising findings; fever by as little as 1-2C is well known to dramatically worsen neurologic outcomes. Given that both temperatures provided similar benefits, and because the application of TTM is associated with fewer adverse side effects than TH, TTM may be the safest therapeutic option for temperature management. Conversely, a key limitation of TTM is that it is not thought to activate additional neuroprotective mechanisms (as does TH). The next advance in temperature management therapy may be to discover drugs which make TTM more neuroprotective (Concept 1), or alternatively (Concept 2) drugs which lessen the systemic side effects of neuroprotective TH. This R21 will test if fibroblast growth factor 21 (FGF21) augments TTM/TH induced neuroprotection in a rat model of pediatric TBI, in part, by upregulating the highly neuroprotective cold- shock protein RNA binding motif 3 (RBM3).